Tobacco addiction is an enormous public health problem. Recent advances in understanding the effects of nicotine on the brain and behavior present an opportunity to advance medication development. Neurotransmission at NMDA receptors is involved in many of nicotine's effects and it is postulated that modulation of NMDA neurotransmission may be effective in the treatment of tobacco addiction. We propose to develop and implement human laboratory models to screen promising medications and establish whether modulation of the NMDA receptor system with memantine, a non-competitive NMDA antagonist, has beneficial effects in the treatment of tobacco addiction. For comparison we will test bupropion, an antidepressant with proven efficacy in the treatment of tobacco addiction. Inpatient laboratory studies will include paradigms designed to model several dimensions of tobacco addiction using non-treatment seeking, nicotine-dependent smokers. We will assess the effect of chronic treatment with bupropion and memantine in two paradigms that model two main components of tobacco addiction that can be a target for pharmacological modulation. In Study 1 we will model maintenance of cigarette smoking, and assess how medications affect: early tobacco withdrawal, effects of cigarettes in smoking-deprived and non-deprived smokers, reactivity to cigarette cues, and cigarette smoking under unlimited choice conditions and under operational conditions (cigarettes versus money choice). In Study 2 we will develop a laboratory model of smoking relapse induced by cigarette exposure in abstinent smokers, and will compare self-administration behavior after the exposure to the neutral or active cigarette stimulus. In Study 3, we will use a smoking relapse model to assess how medication affects extended withdrawal, the effects of cigarettes in deprived smokers, and self-administration behavior in abstinent participants following cigarette re-exposure. At the conclusion of 5 years, we will be able to develop laboratory models for early-stage testing of new and/or existing compounds for the treatment of tobacco addiction and to further elucidate the neurobiology of nicotine dependence in humans, particularly the contribution of NMDA receptor neurotransmission. This application represents, to our knowledge, the first attempt to systematically evaluate the contribution of NMDA receptor-mediated neurotransmission on nicotine's action in humans from the perspective of medication development. [unreadable] [unreadable]